Gemcitabine prodrugs

Abstract

Provided herein are phosphorylated gemcitabine derivative prodrug compounds, pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of cancer.

1 . A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from fatty acid, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides; 
         R 1  is selected from hydrogen, fatty acid, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides; and 
         R 2  is selected from hydrogen, fatty acid, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides. 
       
     
     
         2 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen. 
     
     
         3 . The compound of  claim 1 , or pharmaceutically acceptable salt thereof, wherein R and R1 are independently selected from a fatty acid. 
     
     
         4 . The compound of  claim 3 , or pharmaceutically acceptable salt thereof, wherein the fatty acid is independently selected from the group consisting of a saturated, monounsaturated, polyunsaturated fatty acid, a C2-C26 fatty acid, docosahexaenoic acid, eicosapentaenoic acid, docosahexaenoic acid, eicosapentaenoic acid, oleic acid, stearic acid, (9Z,12Z)-octadeca-9,12-dienoic acid, (Z)-docos-13-enoic acid, docosanoic acid, (E)-octadec-9-enoic acid, icosanoic acid, (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid, palmitic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, nonadecanoic acid, eicosanoic acid, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, crotonic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, nervonic acid, linoleic acid, eicosadienoic acid, docosadienoic acid, linolenic acid, pinolenic acid, eleostearic acid, mead acid, dihomo-γ-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosatetraenoic acid, and adrenic acid. 
     
     
         5 - 12 . (canceled) 
     
     
         13 . A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (II): 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from fatty acid, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides; 
         R 1  is selected from hydrogen, fatty acid, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides; and 
         R 2  is selected from hydrogen, fatty acid, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides. 
       
     
     
         14 . The compound of  claim 13 , or pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen. 
     
     
         15 . The compound of  claim 13 , or pharmaceutically acceptable salt thereof, wherein R and R 1  are independently selected from a fatty acid. 
     
     
         16 . The compound of  claim 15 , or pharmaceutically acceptable salt thereof, wherein each fatty acid is independently selected from a saturated, monounsaturated, polyunsaturated fatty acid, a C2-C26 fatty acid, docosahexaenoic acid, eicosapentaenoic acid, docosahexaenoic acid, eicosapentaenoic acid, oleic acid, stearic acid, (9Z,12Z)-octadeca-9,12-dienoic acid, (Z)-docos-13-enoic acid, docosanoic acid, (E)-octadec-9-enoic acid, icosanoic acid, (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid, palmitic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, nonadecanoic acid, eicosanoic acid, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, crotonic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, nervonic acid, linoleic acid, eicosadienoic acid, docosadienoic acid, linolenic acid, pinolenic acid, eleostearic acid, mead acid, dihomo-γ-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosatetraenoic acid, and adrenic acid. 
     
     
         17 - 24 . (canceled) 
     
     
         25 . A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (III): 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from hydrogen, fatty acid, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides; 
         R 1  is selected from hydrogen, fatty acid, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides; 
         R 2  is selected from hydrogen, fatty acid, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides; 
         L is a linker selected from an alkylene amide group, an alkylene ester group, an alkylene carbamate group, a disulfide group, a phosphodiester group, and a phosphoramidate group; and 
         G is a cytotoxic chemotherapy agent. 
       
     
     
         26 . The compound of  claim 25 , or pharmaceutically acceptable salt thereof, wherein the cytotoxic chemotherapy agent is selected from abiraterone, afatinib, axitinib, azacitidine, bortezomib, cabazitaxel, cabozantinib, capecitabine, carfilzomib, ceritinib, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dactinomycin, dasatinib, daunorubicin, decarbazine, decitabine, docetaxel, doxorubicin, epirubicin, erlotinib, etoposide, everrolimus, floxuridine, gefitinib, ibrutinib, idarubicin, idelalisib, lapatinib, lenvatinib, leucovorin, methotrexate, mitomycin, olaparib, palbociclib, pazopanib, ponatinib, pralatrexate, prednisone, regorafenib, ruxolitinib, sorafenib, streptozocin, sunitinib, thalidomide, topotecan, vemurafenib, vincristine, vinorelbine, and zoledronic acid. 
     
     
         27 . The compound of  claim 25 , or pharmaceutically acceptable salt thereof, wherein L is an alkylene carbamate group. 
     
     
         28 . The compound of  claim 25 , or pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IIIa): 
       
         
           
           
               
               
           
         
         wherein n is 1 to 6. 
       
     
     
         29 . The compound of  claim 25 , or pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen. 
     
     
         30 . The compound of  claim 25 , or pharmaceutically acceptable salt thereof, wherein R and R 1  are independently selected from a fatty acid. 
     
     
         31 . The compound of  claim 30 , or pharmaceutically acceptable salt thereof, wherein the fatty acid is independently selected from the group consisting of a saturated, monounsaturated, polyunsaturated fatty acid, a C2-C26 fatty acid, docosahexaenoic acid, eicosapentaenoic acid, docosahexaenoic acid, eicosapentaenoic acid, oleic acid, stearic acid, (9Z,12Z)-octadeca-9,12-dienoic acid, (Z)-docos-13-enoic acid, docosanoic acid, (E)-octadec-9-enoic acid, icosanoic acid, (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid, palmitic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, nonadecanoic acid, eicosanoic acid, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, crotonic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, nervonic acid, linoleic acid, eicosadienoic acid, docosadienoic acid, linolenic acid, pinolenic acid, eleostearic acid, mead acid, dihomo-γ-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosatetraenoic acid, and adrenic acid. 
     
     
         32 - 54 . (canceled) 
     
     
         55 . A pharmaceutical composition comprising a compound of  claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         56 . The pharmaceutical composition of  claim 55 , wherein the composition is suitable for administration by injection. 
     
     
         57 . The pharmaceutical composition of  claim 56 , wherein the composition is formulated as an albumin-coated nanoparticle or as a lipid-based nanoparticle. 
     
     
         58 - 89 . (canceled)